Recently it was found that people with a small heritable genetic change (known as a single nucleotide polymorphism or SNP) in the DNA sequence of a gene called ITGAM are more likely to have lupus, but it's still not known why this change in DNA increases the risk of disease. It is known that the ITGAM gene encodes part of a protein complex called Mac-1, which is expressed on the surface of blood cells and is essential for their proper function. Mac-1 is important in regulating immune responses to environmental stimuli and is important in the proper adhesion and movement of white blood cells in an inflammatory/immune response. We hypothesize that this SNP, or combinations of SNPs, in the ITGAM gene promote lupus development because they lead to the production of altered Mac-1 proteins which changes blood cell behavior and function. These changes, in response to environmental challenges, contribute to immune responses that predisposes to the development of SLE. Our team plans to test this idea by studying ITGAM DNA and ITGAM protein from blood cells collected from individuals that have these variants. We should be able to establish mechanisms by which ITGAM protein variants contribute to lupus. Once this is established, then we can develop methods to identify people who are at risk of lupus based on expression of ITGAM variant(s), and we further explore the immune pathways that these ITGAM variants affect. We can then consider drugs that specifically target either ITGAM itself or target the pathways that ITGAM variants have an impact on to treat lupus more effectively and safely. We plan to express the variant ITGAM proteins in mice using transgenic technology and test their functional relevance in established murine models of SLE. We believe that the proposed studies will capitalize on the recent genetic findings by elucidating biological mechanisms of causative genetic variants that contribute to SLE pathogenesis. PUBLIC HEALTH RELEVANCE: This project will elucidate mechanisms of recent GWAS and candidate gene based genetic evidence of a role for the ITGAM gene product in the pathogenesis of SLE. SLE is a disease that has both an environmental and genetic basis. Elucidation of the mechanism(s) of action of the genetic variants in SLE will guide future studies in the pathogenesis of and ultimately treatment of this and other inflammatory conditions.